Oncogenic KRAS signalling in pancreatic cancer

British Journal of Cancer

Volumn 111, Issue 5, 2014, Pages 817-822

  Eser, S ^a,b   Schnieke, A ^c   Schneider, G ^a   Saur, D ^a,b  

^a TECHNICAL UNIVERSITY OF MUNICH   (Germany)

^b GERMAN CANCER RESEARCH CENTER DKFZ   (Germany)

^c TECHNICAL UNIVERSITY OF MUNICH   (Germany)

Author keywords

acinar to ductal metaplasia; Akt; glutaminolysis; glycolysis; Kras driven cancer; MAPK; metabolism; non small cell lung cancer; oncogenic Kras; oncogenic Kras signalling; pancreatic cancer; pancreatic intraepithelial neoplasia; Pdk1; PI3K

Indexed keywords

HUMAN; INFLAMMATION; METABOLISM; MOLECULARLY TARGETED THERAPY; NUCLEAR REPROGRAMMING; ONCOGENE K RAS; PANCREAS ADENOCARCINOMA; PANCREAS CANCER; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; TUMOR MICROENVIRONMENT;

ANIMALS; CARCINOMA, PANCREATIC DUCTAL; HUMANS; PANCREATIC NEOPLASMS; PROTO-ONCOGENE PROTEINS; RAS PROTEINS; SIGNAL TRANSDUCTION;

EID: 84906938439     PISSN: 00070920     EISSN: 15321827     Source Type: Journal    
DOI: 10.1038/bjc.2014.215     Document Type: Review

References (53)

1. Aichler M, Seiler C, Tost M, Siveke J, Mazur PK, Da Silva-Buttkus P, Bartsch DK, Langer P, Chiblak S, Durr A, Hofler H, Kloppel G, Muller-Decker K, Brielmeier M, Esposito I (2012) Origin of pancreatic ductal adenocarcinoma from atypical flat lesions: a comparative study in transgenic mice and human tissues. J Pathol 226: 723-734.
2. Ardito CM, Gruner BM, Takeuchi KK, Lubeseder-Martellato C, Teichmann N, Mazur PK, Delgiorno KE, Carpenter ES, Halbrook CJ, Hall JC, Pal D, Briel T, Herner A, Trajkovic-Arsic M, Sipos B, Liou GY, Storz P, Murray NR, Threadgill DW, Sibilia M, Washington MK, Wilson CL, Schmid RM, Raines EW, Crawford HC, Siveke JT (2012) EGF receptor is required for KRAS-induced pancreatic tumorigenesis. Cancer Cell 22: 304-317.
3. Berndt N, Hamilton AD, Sebti SM (2011) Targeting protein prenylation for cancer therapy. Nat Rev Cancer 11: 775-791.
4. Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB, Johns AL, Miller DK, Wilson PJ, Patch AM, Wu J, Chang DK, Cowley MJ, Gardiner BB, Song S, Harliwong I, Idrisoglu S, Nourse C, Nourbakhsh E, Manning S, Wani S, Gongora M, Pajic M, Scarlett CJ, Gill AJ, Pinho AV, Rooman I, Anderson M, Holmes O, Leonard C, Taylor D, Wood S, Xu Q, Nones K, Fink JL, Christ A, Bruxner T, Cloonan N, Kolle G, Newell F, Pinese M, Mead RS, Humphris JL, Kaplan W, Jones MD, Colvin EK, Nagrial AM, Humphrey ES, Chou A, Chin VT, Chantrill LA, Mawson A, Samra JS, Kench JG, Lovell JA, Daly RJ, Merrett ND, Toon C, Epari K, Nguyen NQ, Barbour A, Zeps N, Kakkar N, Zhao F, Wu YQ, Wang M, Muzny DM, Fisher WE, Brunicardi FC, Hodges SE, Reid JG, Drummond J, Chang K, Han Y, Lewis LR, Dinh H, Buhay CJ, Beck T, Timms L, Sam M, Begley K, Brown A, Pai D, Panchal A, Buchner N, De Borja R, Denroche RE, Yung CK, Serra S, Onetto N, Mukhopadhyay D, Tsao MS, Shaw PA, Petersen GM, Gallinger S, Hruban RH, Maitra A, Iacobuzio-Donahue CA, Schulick RD, Wolfgang CL, Morgan RA, Lawlor RT, Capelli P, Corbo V, Scardoni M, Tortora G, Tempero MA, Mann KM, Jenkins NA, Perez-Mancera PA, Adams DJ, Largaespada DA, Wessels LF, Rust AG, Stein LD, Tuveson DA, Copeland NG, Musgrove EA, Scarpa A, Eshleman JR, Hudson TJ, Sutherland RL, Wheeler DA, Pearson JV, McPherson JD, Gibbs RA, Grimmond SM (2012) Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 491: 399-405.
5. Blasco RB, Francoz S, Santamaria D, Canamero M, Dubus P, Charron J, Baccarini M, Barbacid M (2011) c-Raf, but not B-Raf, is essential for development of K-Ras oncogene-driven non-small cell lung carcinoma. Cancer Cell 19: 652-663.
6. Castellano E, Downward J (2011) RAS Interaction with PI3K: more than just another effector pathway. Genes Cancer 2: 261-274.
7. Castellano E, Sheridan C, Thin MZ, Nye E, Spencer-Dene B, Diefenbacher ME, Moore C, Kumar MS, Murillo MM, Gronroos E, Lassailly F, Stamp G, Downward J (2013) Requirement for interaction of PI3-kinase p110alpha with RAS in lung tumor maintenance. Cancer Cell 24: 617-630.
8. Chandarlapaty S (2012) Negative feedback and adaptive resistance to the targeted therapy of cancer. Cancer Discov 2: 311-319.
9. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O'Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364: 2507-2516.
10. Collins MA, Bednar F, Zhang Y, Brisset JC, Galban S, Galban CJ, Rakshit S, Flannagan KS, Adsay NV, Pasca di Magliano M (2012a) Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. J Clin Invest 122: 639-653.
11. Collins MA, Brisset JC, Zhang Y, Bednar F, Pierre J, Heist KA, Galban CJ, Galban S, di Magliano MP (2012b) Metastatic pancreatic cancer is dependent on oncogenic Kras in mice. PLoS One 7: e49707.
12. Collisson EA, Sadanandam A, Olson P, Gibb WJ, Truitt M, Gu S, Cooc J, Weinkle J, Kim GE, Jakkula L, Feiler HS, Ko AH, Olshen AB, Danenberg KL, Tempero MA, Spellman PT, Hanahan D, Gray JW (2011) Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med 17: 500-503.
13. Collisson EA, Trejo CL, Silva JM, Gu S, Korkola JE, Heiser LM, Charles RP, Rabinovich BA, Hann B, Dankort D, Spellman PT, Phillips WA, Gray JW, McMahon M (2012) A central role for RAF-4MEK-4ERK signaling in the genesis of pancreatic ductal adenocarcinoma. Cancer Discov 2: 685-693.
14. Conradt L, Godl K, Schaab C, Tebbe A, Eser S, Diersch S, Michalski CW, Kleeff J, Schnieke A, Schmid RM, Saur D, Schneider G (2011) Disclosure of erlotinib as a multikinase inhibitor in pancreatic ductal adenocarcinoma. Neoplasia 13: 1026-1034.
15. Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardiere C, Bennouna J, Bachet JB, Khemissa-Akouz F, Pere-Verge D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M (2011) FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364: 1817-1825.
16. Corcoran RB, Cheng KA, Hata AN, Faber AC, Ebi H, Coffee EM, Greninger P, Brown RD, Godfrey JT, Cohoon TJ, Song Y, Lifshits E, Hung KE, Shioda T, Dias-Santagata D, Singh A, Settleman J, Benes CH, Mino-Kenudson M, Wong KK, Engelman JA (2013) Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS mutant cancer models. Cancer Cell 23: 121-128.
17. Cowley MJ, Chang DK, Pajic M, Johns AL, Waddell N, Grimmond SM, Biankin AV (2013) Understanding pancreatic cancer genomes. J Hepatobiliary Pancreat Sci 20(6): 549-556.
18. Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, Maira M, McNamara K, Perera SA, Song Y, Chirieac LR, Kaur R, Lightbown A, Simendinger J, Li T, Padera RF, Garcia-Echeverria C, Weissleder R, Mahmood U, Cantley LC, Wong KK (2008) Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 14: 1351-1356.
19. Erkan M, Adler G, Apte MV, Bachem MG, Buchholz M, Detlefsen S, Esposito I, Friess H, Gress TM, Habisch HJ, Hwang RF, Jaster R, Kleeff J, Kloppel G, Kordes C, Logsdon CD, Masamune A, Michalski CW, Oh J, Phillips PA, Pinzani M, Reiser-Erkan C, Tsukamoto H, Wilson J (2012) StellaTUM: current consensus and discussion on pancreatic stellate cell research. Gut 61: 172-178.
20. Eser S, Reiff N, Messer M, Seidler B, Gottschalk K, Dobler M, Hieber M, Arbeiter A, Klein S, Kong B, Michalski CW, Schlitter AM, Esposito I, Kind AJ, Rad L, Schnieke AE, Baccarini M, Alessi DR, Rad R, Schmid RM, Schneider G, Saur D (2013) Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer. Cancer Cell 23: 406-420.
21. Feldmann G, Mishra A, Hong SM, Bisht S, Strock CJ, Ball DW, Goggins M, Maitra A, Nelkin BD (2010) Inhibiting the cyclin-dependent kinase CDK5 blocks pancreatic cancer formation and progression through the suppression of Ras-Ral signaling. Cancer Res 70: 4460-4469.
22. Guerra C, Schuhmacher AJ, Canamero M, Grippo PJ, Verdaguer L, Perez-Gallego L, Dubus P, Sandgren EP, Barbacid M (2007) Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 11: 291-302.
23. Heid I, Lubeseder-Martellato C, Sipos B, Mazur PK, Lesina M, Schmid RM, Siveke JT (2011) Early requirement of Rac1 in a mouse model of pancreatic cancer. Gastroenterology 141: 719-730, 730 e1-7.
24. Hingorani SR, Petricoin EF, Maitra A, Rajapakse V, King C, Jacobetz MA, Ross S, Conrads TP, Veenstra TD, Hitt BA, Kawaguchi Y, Johann D, Liotta LA, Crawford HC, Putt ME, Jacks T, Wright CV, Hruban RH, Lowy AM, Tuveson DA (2003) Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4: 437-450.
25. Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM, Fu B, Lin MT, Calhoun ES, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman JR, Kern SE, Hruban RH, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321: 1801-1806.
26. Kanda M, Matthaei H, Wu J, Hong SM, Yu J, Borges M, Hruban RH, Maitra A, Kinzler K, Vogelstein B, Goggins M (2012) Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia. Gastroenterology 142: 730-733, e9.
27. Karreth FA, Frese KK, DeNicola GM, Baccarini M, Tuveson DA (2011) C-Raf is required for the initiation of lung cancer by K-Ras(G12D). Cancer Discov 1: 128-136.
28. Lim KH, Baines AT, Fiordalisi JJ, Shipitsin M, Feig LA, Cox AD, Der CJ, Counter CM (2005) Activation of RalA is critical for Ras-induced tumorigenesis of human cells. Cancer Cell 7: 533-545.
29. Lim KH, O'Hayer K, Adam SJ, Kendall SD, Campbell PM, Der CJ, Counter CM (2006) Divergent roles for RalA and RalB in malignant growth of human pancreatic carcinoma cells. Curr Biol 16: 2385-2394.
30. Maurer T, Garrenton LS, Oh A, Pitts K, Anderson DJ, Skelton NJ, Fauber BP, Pan B, Malek S, Stokoe D, Ludlam MJ, Bowman KK, Wu J, Giannetti AM, Starovasnik MA, Mellman I, Jackson PK, Rudolph J, Wang W, Fang G (2012) Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity. Proc Natl Acad Sci USA 109: 5299-5304.
31. Moelling K, Schad K, Bosse M, Zimmermann S, Schweneker M (2002) Regulation of Raf-Akt Cross-talk. J Biol Chem 277: 31099-31106.
32. Molina-Arcas M, Hancock DC, Sheridan C, Kumar MS, Downward J (2013) Coordinate direct input of both KRAS and IGF1 receptor to activation of PI3 kinase in KRAS-mutant lung cancer. Cancer Discov 3: 548-563.
33. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25: 1960-1966.
34. Morris JPt, Wang SC, Hebrok M (2010) KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma. Nat Rev Cancer 10: 683-695.
35. Navas C, Hernandez-Porras I, Schuhmacher AJ, Sibilia M, Guerra C, Barbacid M (2012) EGF receptor signaling is essential for k-ras oncogene-driven pancreatic ductal adenocarcinoma. Cancer Cell 22: 318-330.
36. Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM (2013) K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503(7477): 548-551.
37. Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, Beijersbergen RL, Bardelli A, Bernards R (2012) Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 483: 100-103.
38. Pratilas CA, Taylor BS, Ye Q, Viale A, Sander C, Solit DB, Rosen N (2009) V600E)BRAF is associated with disabled feedback inhibition of RAF-MEK signaling and elevated transcriptional output of the pathway. Proc Natl Acad Sci USA 106: 4519-4524.
39. Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D (2011) RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer 11: 761-774.
40. Seidler B, Schmidt A, Mayr U, Nakhai H, Schmid RM, Schneider G, Saur D (2008) A Cre-loxP-based mouse model for conditional somatic gene expression and knockdown in vivo by using avian retroviral vectors. Proc Natl Acad Sci USA 105: 10137-10142.
41. Shimizu T, Tolcher AW, Papadopoulos KP, Beeram M, Rasco DW, Smith LS, Gunn S, Smetzer L, Mays TA, Kaiser B, Wick MJ, Alvarez C, Cavazos A, Mangold GL, Patnaik A (2012) The clinical effect of the dual-targeting strategy involving PI3K/AKT/mTOR and RAS/MEK/ERK pathways in patients with advanced cancer. Clin Cancer Res 18: 2316-2325.
42. Singh A, Greninger P, Rhodes D, Koopman L, Violette S, Bardeesy N, Settleman J (2009) A gene expression signature associated with 'K-Ras addiction' reveals regulators of EMT and tumor cell survival. Cancer Cell 15: 489-500.
43. Son J, Lyssiotis CA, Ying H, Wang X, Hua S, Ligorio M, Perera RM, Ferrone CR, Mullarky E, Shyh-Chang N, Kang Y, Fleming JB, Bardeesy N, Asara JM, Haigis MC, DePinho RA, Cantley LC, Kimmelman AC (2013) Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496: 101-105.
44. Steele CW, Jamieson NB, Evans TR, McKay CJ, Sansom OJ, Morton JP, Carter CR (2013) Exploiting inflammation for therapeutic gain in pancreatic cancer. Br J Cancer 108: 997-1003.
45. Sun Q, Burke JP, Phan J, Burns MC, Olejniczak ET, Waterson AG, Lee T, Rossanese OW, Fesik SW (2012) Discovery of small molecules that bind to K-Ras and inhibit Sos-mediated activation. Angew Chem Int Ed Engl 51: 6140-6143.
46. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF (2013) Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369: 1691-1703.
47. Warburg O (1956) On the origin of cancer cells. Science 123: 309-314.
48. Yadav D, Lowenfels AB (2013) The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology 144: 1252-1261.
49. Ying H, Elpek KG, Vinjamoori A, Zimmerman SM, Chu GC, Yan H, Fletcher-Sananikone E, Zhang H, Liu Y, Wang W, Ren X, Zheng H, Kimmelman AC, Paik JH, Lim C, Perry SR, Jiang S, Malinn B, Protopopov A, Colla S, Xiao Y, Hezel AF, Bardeesy N, Turley SJ, Wang YA, Chin L, Thayer SP, DePinho RA (2011) PTEN is a major tumor suppressor in pancreatic ductal adenocarcinoma and regulates an NF-kappaB-cytokine network. Cancer Discov 1: 158-169.
50. Ying H, Kimmelman AC, Lyssiotis CA, Hua S, Chu GC, Fletcher-Sananikone E, Locasale JW, Son J, Zhang H, Coloff JL, Yan H, Wang W, Chen S, Viale A, Zheng H, Paik JH, Lim C, Guimaraes AR, Martin ES, Chang J, Hezel AF, Perry SR, Hu J, Gan B, Xiao Y, Asara JM, Weissleder R, Wang YA, Chin L, Cantley LC, DePinho RA (2012) Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 149: 656-670.
51. Zimmermann G, Papke B, Ismail S, Vartak N, Chandra A, Hoffmann M, Hahn SA, Triola G, Wittinghofer A, Bastiaens PI, Waldmann H (2013) Small molecule inhibition of the KRAS-PDEdelta interaction impairs oncogenic KRAS signalling. Nature 497: 638-642.
52. Zimmermann S, Moelling K (1999) Phosphorylation and regulation of Raf by Akt (protein kinase B). Science 286: 1741-1744.
53. Zmajkovicova K, Jesenberger V, Catalanotti F, Baumgartner C, Reyes G, Baccarini M (2013) MEK1 is required for PTEN membrane recruitment, AKT regulation, and the maintenance of peripheral tolerance. Mol Cell 50: 43-55.